This project is directed at understanding the mechanisms by which the immune system responds to viral infections. Responses by this system can be divided into components that occur within hours to several days after infection and do not involve antigen-specific responses and later components that involve highly specific responses by T cells and B cells. In many instances, the nonspecific and specific components of the response act synergistically to control infection, but in some cases viruses elicit responses that allow them to evade protective immunity and to persist in the host. We examined the response of mice to infection with mouse cytomegalovirus (MCMV). These studies showed that infection stimulated massive polyclonal B cell activation within 4 days of infection. The response peaked at day 10 and was over by day 14. Activation was associated with increased IgG levels probably secondary to high level expression of interferon gamma. This subversion of the immune system may permit early spread of the virus to the salivary gland where it can remain protected from immune elimination by the late occurring response. We have also initiated studies of another murine herpes virus, MHV-68 a member of the gammaherpesvirus family. This virus targets lung epithelial cells and B cells for infection, develops latency in B cells and appears to contribute to late onset B cell lymphoproliferative disorders. This virus may serve as a small animal model for acute and chronic infections of humans with EBV.